Cyclophosphamide

DRUG NAME: Cyclophosphamide

SYNONYM: Cyclo, CPA, CPM, CTX, CYC, CYT

COMMON TRADE NAME: CYTOXAN®,1 PROCYTOX®, NEOSAR® (USA)

CLASSIFICATION: Alkylating agent

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:
2
Cyclophosphamide is an alkylating agent of the nitrogen mustard type. An activated form of cyclophosphamide,
phosphoramide mustard, alkylates, or binds, to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of
DNA and RNA, and to inhibition of protein synthesis.3 These actions do not appear to be cell-cycle specific.

PHARMACOKINETICS:

Interpatient variability metabolism; clearance of cyclophosphamide and its metabolites4

Oral Absorption >75%2; manufacturer recommends drug be taken on an empty stomach, but states may be
taken with food to decrease GI upset5
time to peak plasma 1-2 h3
concentration
Distribution throughout body
cross blood brain barrier? to limited extent2
volume of distribution 0.56 L/kg6
plasma protein binding7 12-14% of unchanged drug; 67% of total plasma
alkylating metabolites6
Metabolism mainly by microsomal enzymes in the liver;8 cytochrome P450 (CYP) primarily CYP 2B69
active metabolites4 4-hydroxycyclophosphamide, aldophosphamide,
phosphoramide mustard, acrolein10
4
inactive metabolites 4-keto-cyclophosphamide, carboxyphosphamide,
nornitrogen mustard
Excretion primarily by enzymatic oxidation to active and inactive metabolites, which are mainly
excreted in the urine7
urine 5-25% unchanged2
feces 31-66% after oral dose
terminal half life7 6.5 h (1.8-12.4 h)
7
clearance 1.17 mL/min/kg
Gender no clinically important differences found
Elderly no clinically important differences found
Children terminal half life 2.4-6.5 h7; volume of distribution 0.67 L/kg7
Ethnicity no clinically important differences found
11
Adapted from standard reference unless specified otherwise.

BC Cancer Agency Cancer Drug Manual© Page 1 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

USES:
Primary uses: Other uses:
12
*Breast cancer Bladder cancer
12
Conditioning regimen for stem cell transplant Brain cancer
12
Ewing’s sarcoma Cervical cancer
*Leukemia, acute myelogenous Endometrial cancer11
12
*Leukemia, chronic lymphocytic Gestational trophoblastic neoplasia
*Leukemia, chronic myelogenous Leukemia, acute lymphocytic12
11
*Leukemia, pediatric acute lymphoblastic Lymphoma, cutaneous T-cell
*Lung cancer Osteosarcoma12
12
*Lymphoma, Burkitt’s Soft tissue sarcoma
12
*Lymphoma, Hodgkin’s disease Testicular cancer
12
*Lymphoma, non-Hodgkin’s Thymoma
12
Lymphoproliferative disease Waldenstrom’s macroglobulinemia
*Multiple myeloma Wilm’s tumour11
*Mycosis fungoides
*Neuroblastoma
*Ovarian cancer
*Retinoblastoma
Rhabdomyosarcoma
*Health Canada approved indication

SPECIAL PRECAUTIONS:
2
Contraindicated in patients who have a history of hypersensitivity reaction to cyclophosphamide. There is possible
1
cross-sensitivity with other alkylating agents.

Carcinogenicity: Secondary malignancies have developed in patients treated with cyclophosphamide alone or in
combination with other antineoplastics. Occurring most frequently are bladder, myeloproliferative and
lymphoproliferative malignancies. Secondary malignancies are most common in patients treated initially for
myeloproliferative or lymphoproliferative diseases or for non-malignant conditions with immune pathology. Urinary
bladder malignancies are most common in patients who experienced hemorrhagic cystitis.

Mutagenicity: Because of the mutagenic potential of cyclophosphamide, adequate methods of contraception should
1
be used by patients (both male and female) during and at least four months after treatment.

Fertility: Gonadal suppression may occur and sterility can be irreversible in some patients.2 Age and duration of
chemotherapy are the main factors contributing to ovarian failure.13 For example, treatment with cyclophosphamide,
methotrexate and fluorouracil for six months results in permanent ovarian failure in 70 percent of women over 40
years of age and in 40 percent of younger women. The median time to onset of ovarian failure is shorter in older
women than in younger women (2-4 months vs. 6-16 months), and ovarian failure is less likely to be reversible in
older women (in about 10 percent vs. up to 50 percent). The rate of permanent ovarian failure is lower with regimens
of doxorubicin and cyclophosphamide than with cyclophosphamide, methotrexate and fluorouracil.

Heart disease: Caution should be used when treating patients with cyclophosphamide who have pre-existing heart
6
disease.
2
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use
in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for
a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding should be terminated prior to initiating cyclophosphamide therapy as this drug is excreted in breast
milk.1

BC Cancer Agency Cancer Drug Manual© Page 2 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be
clinically important.14

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

allergy/immunology anaphylactic reaction15

nasal congestion when IV doses are administered too rapidly (large doses via 30-60
15
minute infusion); patients experience runny eyes, rhinorrhea, sinus congestion, and
sneezing immediately after infusion15 (1-10%)
blood/bone marrow/ anemia
febrile neutropenia
methemoglobinemia with bone marrow transplant (BMT) doses15
myelosuppression; WBC nadir 8-15 days, platelet nadir 10-15 days, recovery 17-28
days
thrombocytopenia
cardiovascular cardiac dysfunction in high-dose (<1%);15 high-dose can be defined as 60 mg/kg
daily or 120-270 mg/kg over a few days;11 manifests as CHF; cardiac necrosis or
hemorrhagic myocarditis; pericardial tamponade (BMT doses)15
coagulation hypoprothrombinemia, risk of bleeding (very rare)
constitutional symptoms asthenia or sweating (0.1-1%)
dizziness15 (<1%)
dermatology/skin extravasation hazard: none16
alopecia7,15 (40-60%); begins 3-6 weeks after start of therapy
facial flushing following IV administration2,15 (1-10%)
hyperpigmentation (skin and nails)2,15 (<1%)
rash, hives, or itching2,15 (1-5%)
redness, swelling, or pain at injection site2,15
toxic epidermal necrolysis15 (<1%)
endocrine hyperglycemia2
gastrointestinal emetogenic potential: >1g high moderate; <1g low moderate17
anorexia (33%)
diarrhea15 (>10%)
hemorrhagic colitis15 (<1%)
mucositis15 (>10%)
myxedema or sore lips2 (0.1-11%)
nausea and vomiting are dose-related15: > 90% for >1500 mg/m2, 60-90% for 750-
1500 mg/m2, 30-60% for < 750 mg/m2 or oral; usually beginning 6-10 hours after
administration
stomatitis2,15 (>10%)
hepatic hepatotoxicity15 (<1%)

BC Cancer Agency Cancer Drug Manual© Page 3 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

jaundice15 (<1%)
metabolic/laboratory hyperkalemia, usually in context of tumour lysis15 (<1%)
hyperuricemia with high-dose and/or long-term therapy15 (<1%)
syndrome of inappropriate antidiuretic hormone (SIADH) causing hyponatremia
pain headache2,15 (1-10%)
pulmonary interstitial pulmonary fibrosis, with high-dose and/or long-term therapy15 (<1%)
pneumonitis, with high-dose and/or long-term therapy15 (<1%)
renal/genitourinary non-hemorrhagic cystitis6
hemorrhagic cystitis (up to 40%)15; with high-dose and/or long term therapy2;
severe, potentially fatal
renal tubular necrosis15 (1-5%)
hemorrhagic ureteritis (<1%)
secondary malignancy urinary bladder, myeloproliferative, or lymphoproliferative malignancies15 (<1%)
15
sexual/reproductive interferes with oogenesis and spermatogenesis (>10%); may be irreversible in some
function patients; gonadal suppression (amenorrhea)2
syndromes syndrome of inappropriate antidiuretic hormone (SIADH) secretion with high-dose
and/or long-term therapy2,15 (1-5%)
1,11
Adapted from standard reference unless specified otherwise.

Cardiac toxicity may occur in patients receiving high-dose cyclophosphamide. High-dose can be defined as 60
mg/kg daily or 120-270 mg/kg over a few days.11 Other risk factors for developing cardiac toxicity include previous
chest or mediastinal radiotherapy, anthracycline administration, concomitant administration of chemotherapy drugs
which are not normally considered cardiotoxic, especially carmustine, cytarabine, and 6-thioguanine,4 and by the
18
presence of left ventricular dysfunction (ejection fraction less than 50%). The mechanism may involve direct injury
to the endothelium by phosphoramide mustard, an active metabolite of cyclophosphamide.18,19 Unlike
4,18,20
anthracyclines, cyclophosphamide-induced cardiotoxicity does not appear to be cumulative. In contrast to
anthracycline-induced cardiomyopathy which occurs months to years after cumulative doses of anthracyclines,
cyclophosphamide-induced cardiotoxicity occurs much earlier.19 Toxicity has ranged from minor, transient ECG
changes and asymptomatic elevation of cardiac enzymes at a total dose of 100 mg/kg to fatal myocarditis and
4
myocardial necrosis at total doses ranging upwards from 144 mg/kg delivered over 4 days. Clinical signs include
dyspnea, tachypnea, fluid retention, increased systemic venous pressure and shock.21 Patients may experience
21
heart failure, arrhythmias, irreversible cardiomyopathy, pericarditis, or death as a result of cardiotoxicity. Treatment
is supportive.4

Hemorrhagic cystitis may occur in up to 40% of patients (especially children) on long term or high dose
6,11
cyclophosphamide therapy. Other risk factors for developing hemorrhagic cystitis include rate of infusion, and rate
of metabolism of cyclophosphamide, as well as the hydration status, urine output, frequency of urination, and
concurrent exposure to other urotoxic drugs or genitourinary radiotherapy.22 The mechanism may involve direct
injury to the urothelium by acrolein, an active metabolite of cyclophosphamide.10 Hemorrhagic cystitis can develop
2
within a few hours or be delayed several weeks. Clinical diagnosis includes non-specific symptoms such as
hematuria, dysuria, urgency and increased frequency of urination and can be confirmed using cystoscopy.22 Severe
hemorrhagic cystitis can lead to constriction of the bladder, anemia, recurrent urinary tract infection, bladder
perforation, renal failure and death.22 Longterm complications include bladder fibrosis and contraction, urinary reflux
and transitional cell bladder tumours. Non-hemorrhagic cystitis, edema of the bladder and suburethral bleeding can
6
also occur.

BC Cancer Agency Cancer Drug Manual© Page 4 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

Prophylactic measures include encouraging patients to drink plenty of fluids during therapy (most adults will require
15
at least 2 L/day), to void frequently, and to avoid taking the drug at night. Patients should be well hydrated before
and for 24-72 hours following treatment.22 As well, cyclophosphamide should be administered as early in the day as
2
possible to decrease the amount of drug remaining in the bladder overnight. With large IV doses, IV hydration is
usually recommended.15 The use of mesna and/or continuous bladder irrigation is rarely needed for doses <2g/m2.15
However, mesna has been used in patients receiving cyclophosphamide for immunologically mediated disorders
11
(e.g., Wegener’s granulomatosis, systemic lupus erythromatosus, dermatomyositis, polyarteritis). Further
measures to reduce the incidence of cystitis include catheter bladder drainage, bladder irrigation, intravenous
hydration with diuresis, hyperhydration, and the administration of mesna. Hyperhydration is generally not
recommended as it places the patient at risk for fluid overload and electrolyte imbalance, particularly given the
antidiuretic effect of cyclophosphamide.22 Diuretics may be indicated if urine production declines to <100 mL/m2/h. It
appears that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced cystitis in the
BMT population.

Treatment of hemorrhagic cystitis11,22 begins with discontinuation of cyclophosphamide. Fluid intake should be
3
increased and the platelet count should be maintained at >50 000/mm to minimize the extent of bleeding. There are
several treatment options currently advocated, depending on the severity of bleeding.

Treatment of early cystitis23:

 The first line therapy is to administer hyperhydration. Standard hyperhydration may consist of NS or 1/2 NS
at a rate of 3.0 L/m2 per 24-hour period. Depending on the patient’s electrolyte status, KCl and MgS04 are
generally added to the fluid at concentrations 20-40 mEq/L and 2-4 g/L respectively. Patients who have
visible clots in the urine, or have bladder spasms should receive continuous bladder irrigation. Treatment is
generally continued for 48 hours after the urine returns to normal colour and the symptoms have resolved.
 The second line therapy is to initiate a bladder irrigation with Alum (aluminum potassium sulphate) which is
prepared by pharmacy as a 1% solution for intravesical administration. This is instilled at a rate of 300-1000
mL/hour and the rate is adjusted to maintain clear pink drainage. Responses to Alum are improved
following removal of clots in the bladder using either cystoscopy or irrigation prior to therapy. As Alum
contains significant amounts of aluminum, aluminum levels should be taken in patients with renal
impairment, or in patients requiring prolonged therapy.
 The third line therapy is with prostaglandin (carboprost) which is thought to stimulate platelet aggregation
and cause local vasoconstriction. The dose is generally 0.8-1.0 mg/dL in 50 mL NS (400-500 mcg) instilled
into the bladder; clamp catheter and allow solution to dwell for 60 minutes; repeat every six hours until
23
response. Like Alum, this therapy works best when the bladder is evacuated of clots before starting.
Patients who respond will do so by 5-7 days. Carboprost can cause intense bladder spasm and this can be
a major problem. Therapy with oxybutinin, Belladonna and opium suppositories, or systemic narcotic
analgesics may be necessary. In rare cases, hemorrhagic cystitis is resistant to the above treatments and
bladder fulguration with formalin or other chemicals is needed.
23
Treatment of late onset cystitis :
Many of these cases are due to secondary viral infection or bacterial infection of the injured mucosa. Culture for
bacterial pathogens, cytomegalovirus (CMV) and adenovirus should be done before starting therapy. Primary
therapy is hyperhydration, possibly with bladder irrigation. Patients may be need to be treated if pathogen is found
(i.e., ganciclovir or foscarnet for CMV, ribavirin for adenovirus, antibiotics for bacterial infections).

Immunogenicity: Positive reactions to skin test antigens (e.g., tuberculin purified protein derivative, trichophyton,
candida) are frequently suppressed in patients receiving cyclophosphamide.11

Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or
24
acute renal failure. It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-
grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal
dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients25:
 aggressive hydration: 3 L/m²/24 hr with target urine output >100 ml/h
 if possible, discontinue drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
 monitor electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours
 replace electrolytes as required
 allopurinol 600 mg po initially, then 300 mg po q6h x6 doses, then 300 mg po daily x 5-7 days

BC Cancer Agency Cancer Drug Manual© Page 5 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to
maintain urine pH>7. Rasburicase (FASTURTEC®) is a novel uricolytic agent that catalyzes the oxidation of uric
acid to a water-soluble metabolite, removing the need for alkalinization of the urine.26 It may be used for treatment or
prophylaxis of hyperuricemia; however, its place in therapy has not yet been established. Aluminium hydroxide
(AMPHOGEL®) may be added orally if phosphate becomes elevated. If aluminium hydroxide has been added,
27
discontinue sodium bicarbonate.

Interstitial pulmonary fibrosis11,28 may occur in patients receiving high doses of cyclophosphamide over prolonged
periods. Other risk factors include exposure to other drugs with pulmonary toxicities and pulmonary radiotherapy.
The mechanism may involve direct injury to the pulmonary epithelium by cyclophosphamide metabolites.28 In some
cases discontinuation of the drug and initiating corticosteroid therapy fails to reverse this condition, which can be
fatal. Signs and symptoms typically include tachycardia, dyspnea, fever, non-productive cough, basilar crepitant
rales, interstitial bilateral infiltrates on chest x-ray, hypoxemia and ventilation/perfusion dysfunction. Interstitial
pneumonitis has also been reported in patients receiving cyclophosphamide. The drug should be stopped at the first
sign of pulmonary toxicity; all other possible causes of pneumonitis should be ruled out.

Nasal stuffiness or facial discomfort may occur. This nasopharyngeal discomfort “wasabi nose” may be
29-31
associated with rapid injection of cyclophosphamide. This reaction may be caused by a mucosal inflammatory
32
response or possibly a cholinergic mechanism. If troublesome for the patient, several interventions have been
32
used : the slowing down of the infusion rate or giving as an intermittent infusion rather than as an IV bolus, the use
of analgesics, decongestants, antihistamines, intranasal beclomethasone, or intranasal ipratropium.

Radiation recall reactions2: Cyclophosphamide has the potential to enhance radiation injury to tissues; this is a
rare side effect. While often called radiation recall reactions, the timing of the radiation may be before, concurrent
with, or even after the administration of the cyclophosphamide. Recurrent injury to a previously radiated site may
occur weeks to months following the radiation.

SIADH (syndrome of inappropriate secretion of ADH)1 may occur in patients receiving cyclophosphamide,
resulting in hyponatremia, dizziness, confusion or agitation, unusual tiredness or weakness. This syndrome is more
common with doses >50 mg/kg and may be aggravated by administration of large volumes of fluids to prevent
hemorrhagic cystitis.8 The condition is self-limiting although diuretic therapy may be helpful in the situation when the
patient has stopped urinating (especially if this occurs during the first 24 hours of cyclophosphamide therapy).
Susceptible patients should be monitored for cardiac decompensation. If weight gain is excessive (1.5-2 kg) during
hydration, the volume of IV fluid should be reduced.
1
Secondary malignancies have developed in some patients, often several years after administration. The most
frequently reported neoplasms are urinary bladder cancer, non-lymphocytic leukemia and non-Hodgkin's lymphoma.
Urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis.6

Water retention and dilutional hyponatremia: Administration of cyclophosphamide in doses higher than 30-40
mg/kg has been associated with water retention and dilutional hyponatremia.8,11 Children may be especially
susceptible. The mechanism is related to direct injury to the distal renal tubules and collecting ducts by
cyclophosphamide metabolites. Symptoms include decreased urine flow, decreased serum osmolarity and sodium,
and increased urine osmolarity. These can occur 4 to 12 hours after cyclophosphamide and resolve within 20 to 24
hours after therapy.

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT

allopurinol delayed, moderate; unknown frequent monitoring with a
increased complete blood count may
myelosuppressive effects be required
of cyclophosphamide is
possible

BC Cancer Agency Cancer Drug Manual© Page 6 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013

AGENT EFFECT
33
amiodarone increased risk of
pulmonary fibrosis
chloramphenicol delayed, moderate;
decrease or delay in
activation of
cyclophosphamide
ciprofloxacin35 delayed, moderate;
decreased antimicrobial
effect of quinolone
antibiotics is possible
corticosteroids decreased or increased
effect of
cyclophosphamide
digoxin delayed, moderate;
reduced serum levels of
digoxin is suspected
grapefruit juice40 delayed, moderate;
decreased or delayed
activation of
cyclophosphamide
hydrochlorothiazide42,43 myelosuppressive effects
of cyclophosphamide may
be increased
indapamide delayed, moderate;
prolonged leucopenia is
possible
indomethacin6 4 cases of severe
pulmonary edema and
acute life-threatening
water intoxication
phenytoin9, phenobarbital, increased rate at which
rifampin and other drugs cyclophosphamide is
which induce CYP2B644 converted to active and
toxic metabolites and
possibly to inactive
metabolites
succinylcholine rapid, moderate;
prolonged neuromuscular
blockade produced by
succinylcholine is probable
warfarin delayed, moderate;
increased anticoagulant
effect of warfarin
suspected
35
Adapted from standard reference unless specified otherwise.
BC Cancer Agency Cancer Drug Manual© Page 7 of 12
Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
MECHANISM
unknown, possibly additive
effect
inhibition (weak) of the
CYP2C8/9 and CYP3A4
enzymes by
chloramphenicol33,34
decreased quinolone
absorption by altering the
intestinal mucosa
induction (weak) of the
CYP3A4 enzyme by
corticosteroids15,37-39
drug-induced alterations of
the intestinal mucosa may
be involved
inhibition (moderate) of the
CYP3A4 enzyme15,41 by
grapefruit juice
unknown
unknown
unknown
induction (strong) of the
CYP2B6 enyzme15,44 by
phenytoin, phenobarbital
and rifampin.
cyclophosphamide inhibits
plasma cholinesterase
resulting in decreased
metabolism of
succinylcholine
inhibition of warfarin
metabolism, or clotting
factor synthesis
Cyclophosphamide
MANAGEMENT
avoid combination if
possible; otherwise
increase monitoring
standard monitoring
procedures for both drugs
ciprofloxacin can be used
as a prophylactic antibiotic
in cyclophosphamide
36
based regimens.
consider monitoring
ciprofloxacin therapy.
clinical significance of this
interaction is unlikely
based on evidence
available; observe for
altered effect of
cyclophosphamide.
monitoring for reduced
digoxin effect
avoid grapefruit juice for
48 hours before and on
day of dose
monitor for
myelosuppression;
consider alternative
antihypertensive therapy
avoid concurrent use;
consider alternative
antihypertensive therapy
avoid concurrent use
clinical significance of this
interaction is unknown;
observe for altered effect
of cyclophosphamide
consider reducing
succinylcholine based on
measured plasma
cholinesterase levels
monitoring coagulation
parameters during and
after chemotherapy; adjust
warfarin dose as needed
Cyclophosphamide
 Cyclophosphamide

SUPPLY AND STORAGE:

Oral6: Store at room temperature.

CYTOXAN® available as 25 mg and 50 mg white tablets with blue flecks.
PROCYTOX® available as 25 mg and 50 mg white to off-white, sugar-coated tablet.

Injection6: Store at room temperature.

CYTOXAN® available as a non-lyophilized formulation manufactured by Bristol-Myers Squibb;1 available in single-
use vials of 1000 mg and 2000 mg. Contains no preservative. Protect from light.
45
PROCYTOX® available as a non-lyophilized formulation manufactured by Baxter; available in 200 mg, 500 mg,
1000 mg and 2000 mg vials. Contains no preservative. Protect from light.

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation
and Stability Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation
and Stability Chart in Appendix.

Compatibility: consult detailed reference

Additional information: Cyclophosphamide oral suspension may be prepared using the intravenous formulation.
Reconstitute vials with normal saline to a concentration of 20 mg/mL. Withdraw vial contents and dilute 1:1 with
suspending vehicle (simple syrup or ORA-PLUS®). Prepared suspensions in either suspending vehicle are stable 2
months in the refrigerator. When stored at room temperature, simple syrup preparations are stable 3 days and ORA-
46
PLUS® preparations are stable 8 days.

PARENTERAL ADMINISTRATION:

BCCA administration guideline noted in bold, italics

Subcutaneous no information found
Intramuscular has been used
Direct intravenous each 100 mg or fraction thereof over at least 1
minute
Intermittent infusion in 50-100 mL of compatible IV solution over 20-60
minutes
Continuous infusion the dose can be administered in a convenient
volume
Intraperitoneal has been used but not recommended due to need for
metabolic activation11
Intrapleural has been used but not recommended due to need for
metabolic activation11
Intrathecal no information found; metabolic activation required11
Intra-arterial no information found
Intravesical no information found

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count.
Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation
therapy or with other toxicities.

BC Cancer Agency Cancer Drug Manual© Page 8 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

Adults:
BCCA usual dose noted in bold, italics
Cycle Length:
Oral: 4 weeks36,47 100 mg/m2 (range 75-100 mg/m2) once daily for 14
consecutive days
2
(total dose per cycle 1400 mg/m )

3-4 weeks47: 300 mg/m2 (range 200-450 mg/m2) once daily for 5
consecutive days. (total dose per cycle 1500 mg/m2
[range 1000-2250 mg/m2])

Round dose to the nearest 25 mg. The manufacturer recommends that the drug be taken on an empty stomach, but
states it may be taken with food to decrease GI upset.5

Intravenous: 3 weeks48-51 600 mg/m2 (range 500-1000 mg/m2) for one dose on
day 1

4 weeks52: 1000 mg/m2 for one dose on day 1

6 weeks53: 1200 mg/m2 for one dose on day 1

4 weeks36: 525 mg/m2 for one dose on day 1 and day 15

(total dose per cycle 1050 mg/m2)

4 weeks54: 1200 mg/m2 for one dose on day 1 and day 8

2
(total dose per cycle 2400 mg/m )

11 weeks50: 1000 mg/m2 for one dose on day 1 and day 56

(total dose per cycle 2000 mg/m2)

High dose protocols with or 60 mg/kg for one dose on day -3 and day -255
without bone marrow transplant: (total dose 120 mg/kg over 2 days)
note: ideal body weight is often
used.

50 mg/kg for one dose on day -6, day -5 and day -456
(total dose 150 mg/kg over 3 days)

2700 mg/m2 for one dose on day 1 and day 257

2
(total dose 5400 mg/m over 2 days)

2500 mg/m2 for one dose on day 1

1800 mg/m2 once daily for five consecutive days starting

58
on day -5
(total dose 7200 mg/m2 over 4 days)

1800 mg/m2 for one dose on day -6, day -5, day -4 and day
59,60
-3
(total dose 7200 mg/m2over 4 days)

2000 mg/m2 for one dose on day 3, day 4 and day 561
2
(total dose 6000 mg/m over 3 days)

1000 mg/m2for one dose on day 1 and day 262

2
(total dose 2000 mg/m over 2 days)

BC Cancer Agency Cancer Drug Manual© Page 9 of 12 Cyclophosphamide

Developed: September 1994
Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013
 Cyclophosphamide

Concurrent radiation: infrequently radiation is given during treatment53,63 ; more often given following
36,64-70
chemotherapy

Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure: Suggested dose modifications71:

Creatinine clearance Cyclophosphamide
(mL/min) dose
> 10 100%
<10 75%

Calculated creatinine clearance = N* x (140 - Age) x weight

Serum Creatinine in µmol/L
* For males N = 1.23; for females N = 1.04

Dosage in hepatic failure: no adjustment required

Dosage in dialysis: dialyzable with a high extraction efficiency7

hemodialysis: ½ dose has been suggested71

there have been 2 case reports of giving high-dose cyclophosphamide with
continuous bladder irrigation +/- mesna.72,73 Hemodialysis (duration 6 h) was
72 73
performed 6 h and 14 h after cyclophosphamide infusion. Dialysis should not
be started sooner then 12 h after cyclophosphamide infusion.74

chronic ambulatory peritoneal dialysis (CAPD): dose as for GFR < 10

2 75
mL/min/1.73m (i.e., administer 75% of dose)

continuous arteriovenous or venovenous hemofiltration (CAVH): dose as for

GFR 10-50 mL/min/1.73m2 (i.e., administer 100% dose)71

Children76,77:
Cycle Length:
2
Oral: daily: 50-300 mg/m

Intravenous: 3-4 weeks76 250-1800 mg/m2 for one dose on day 1, day 2, day 3 and
day 4
77
3-4 weeks : up to 2000-3000 mg/m2 for one dose on day 1

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BC Cancer Agency Cancer Drug Manual© Page 12 of 12 Cyclophosphamide

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Limited Revision: March 2006, August 2006, 1 June 2011, 1 October 2011, 1 June 2013